MUTYH promotes oxidative microglial activation and inherited retinal degeneration
Shunji Nakatake, Yusuke Murakami, Yasuhiro Ikeda, Noriko Morioka, Takashi Tachibana, Kohta Fujiwara, Noriko Yoshida, Shoji Notomi, Toshio Hisatomi, Shigeo Yoshida, Tatsuro Ishibashi, Yusaku Nakabeppu, Koh-Hei Sonoda
Shunji Nakatake, Yusuke Murakami, Yasuhiro Ikeda, Noriko Morioka, Takashi Tachibana, Kohta Fujiwara, Noriko Yoshida, Shoji Notomi, Toshio Hisatomi, Shigeo Yoshida, Tatsuro Ishibashi, Yusaku Nakabeppu, Koh-Hei Sonoda
View: Text | PDF
Research Article Inflammation Ophthalmology

MUTYH promotes oxidative microglial activation and inherited retinal degeneration

Abstract

Oxidative stress is implicated in various neurodegenerative disorders, including retinitis pigmentosa (RP), an inherited disease that causes blindness. The biological and cellular mechanisms by which oxidative stress mediates neuronal cell death are largely unknown. In a mouse model of RP (rd10 mice), we show that oxidative DNA damage activates microglia through MutY homolog–mediated (MUYTH-mediated) base excision repair (BER), thereby exacerbating retinal inflammation and degeneration. In the early stage of retinal degeneration, oxidative DNA damage accumulated in the microglia and caused single-strand breaks (SSBs) and poly(ADP-ribose) polymerase activation. In contrast, Mutyh deficiency in rd10 mice prevented SSB formation in microglia, which in turn suppressed microglial activation and photoreceptor cell death. Moreover, Mutyh-deficient primary microglial cells attenuated the polarization to the inflammatory and cytotoxic phenotype under oxidative stress. Thus, MUTYH-mediated BER in oxidative microglial activation may be a novel target to dampen the disease progression in RP and other neurodegenerative disorders that are associated with oxidative stress.

Authors

Shunji Nakatake, Yusuke Murakami, Yasuhiro Ikeda, Noriko Morioka, Takashi Tachibana, Kohta Fujiwara, Noriko Yoshida, Shoji Notomi, Toshio Hisatomi, Shigeo Yoshida, Tatsuro Ishibashi, Yusaku Nakabeppu, Koh-Hei Sonoda

×

Figure 3

Mutyh deficiency suppressed the expansion of retinal oxidative DNA damage in rd10 mice.

Options: View larger image (or click on image) Download as PowerPoint
Mutyh deficiency suppressed the expansion of retinal oxidative DNA dama...
(A–C) Immunohistochemical detection of 8-oxoG in the retina of P14, P17, and P21 rd10;Mutyh+/+ mice or rd10;Mutyh−/− mice. HCl pretreatment was used for denaturing the nuclear DNA, thereby enhancing the detection of 8-oxoG in nuclear DNA. The accumulation of 8-oxoG was not observed in the retinas of the rd10;Mutyh+/+ mice or rd10;Mutyh−/− mice at P14 (A). Scattered accumulation of 8-oxoG was observed at P17 (arrows), and the staining pattern was comparable between the rd10;Mutyh+/+ mice and rd10;Mutyh−/− mice (B). The 8-oxoG accumulation was expanded to the ONL diffusely at P21 rd10;Mutyh+/+ mice (arrowheads), whereas it was substantially suppressed in rd10;Mutyh−/− mice (arrows) (C). INL, inner nuclear layer; ONL, outer nuclear layer. Scale bar: 50 μm. Figures show the representative results from 3 experiments.